The present invention relates to a method of treatment or prevention of tension-type headache in a human in need of such treatment. In particular, the invention relates to a method of treatment of tension-type headache comprising the administration of an agent or agents effective for the prevention or reduction of central sensitization
Previously, headache disorders were not clearly distinguished and it was widely believed that they formed part of a continuum and were strongly related. In 1988, The International Headache Society, (IHS) via its ad hoc committee on classification published a document entitled Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain (Classification and Diagnostic Criteria for Headache Disorders, 1988). A new entity was here defined by name of tension-type headache. This entity was practically the same as conditions previously called tension headache, muscle contraction headache, psycho-myogenic headache and idiopathic headache. The IHS classification also defined a number of other specific headache diseases. Today it therefore gives no meaning to talk about headache in general. It would be the same as to discuss bellyache and chest pain without specifying its type and etiology. Due to the development in diagnostic accuracy research results obtained before 1988 have uncertain validity.
Tension-type headache was subdivided by the IHS Classification Committee into an episodic form occurring less than half of all days and a chronic form occurring half of all days or more. Furthermore, both of these divisions were further subdivided into a form with disorder of pericranial muscle and a form without such disorder. It is thus crucial that research and patents specify which of the subforms are included.
Before the entity of tension-type headache was created, it was widely believed that this kind of headache was caused by muscle ischemia, a concept later disproven by the present inventors (Langemark et al. 1990). The term tension-type headache was created in order to indicate that experts disagreed with the notion of tension-type headache being simply a kind of muscle pain. In fact, the term idiopathic headache was suggested. There is only a moderate co-morbidity with neck pain and low back pain in sufferers of tension-type headache. Furthermore, Electromyography (EMG)-measurements have failed to detect an increase of muscle contraction sufficient to cause pain on a purely mechanical basis in tension-type headache patients whereas central factors such as depression and anxiety have been attributed a significant role. Finally, a genetic factor has recently been shown to be involved in tension-type headache (Østergaard et al. 1996). From the point of view of mechanisms and definition tension-type headache is thus a specific entity which may or may not share mechanisms with muscle pain in the head and in other parts of the body. The classification and diagnostic criteria for tension-type headache are shown in Tables I and II.
Epidemiological studies done by the inventors have shown that chronic tension-type headache affects three percent of the population at any given time, the lifetime prevalence being as high as six percent (Rasmussen et al. 1991). Severe episodic tension-type headache defined as persons having headache twice a week or more occurs in approximately ten percent of the population. Thus, tension-type headache is a serious problem with significant socio-economic implications, involving enormous loss of workdays and quality of life.
The possible pathogenic mechanisms of tension-type headache have previously been studied and discussed by Langemark et al. (Langemark et al. 1987, 1988, 1989) and by the group of Jean Schoenen (Schoenen et al. 1937, 1991a, b). The latter group have mainly focused on electrophysiological recordings as electromyography, and the jaw opening reflex as reflected by the so-called exteroceptive silent period (ES2) (Schoenen et al. 1987). On the basis of shortened ES2 periods in patients with chronic tension-type headache compared to healthy controls a limbic dysfunction was suggested, but these results have later been disproven by more systematic investigations (Bendtsen et al. 1996a, Lipchik et al 1996, Zwart and Sand, 1996). Schoenen and other groups have also studied mechanical pain thresholds on the extremities as well as in the cranial region and decreased mechanical pain thresholds in severely affected patients with chronic tension-type headache were reported (Schoenen et al. 1991a, Langemark et al. 1989), whereas patients with the episodic form of tension-type headache are reported to have normal thresholds compared to healthy controls (Hatch et al. 1992, Goebel et al. 1992, Jensen et al. 1993b). These authors suggested that central mechanisms may be involved in the chronic subform and that the peripheral mechanisms played a role in the episodic form, but provided no further clues or arguments about the underlying mechanisms. One more recent congress presentation and two scientific papers by the present inventors have focused on the sensory mechanisms in tension-type headache as decreased thresholds and tolerances were found in and outside the head of patients with chronic tension-tape headache indicating a generally increased sensitivity to noxious and innocuous stimuli (Bendtsen et al. 1995b, 1996b and 1996c). Similarly a congress report and a scientific paper present data from patients studied during and outside a spontaneous tension-type headache episode (Jensen et al. 1995a and 1995b). Muscle tenderness was increased during the headache episode, whereas mechanical pain thresholds remained unchanged and thermal pain tolerance decreased. It was concluded that a peripheral sensitization may be one of the primary sources of pain and that central sensitization may contribute to and maintain the pain in chronic tension-type headache. However, these data did not provide any further clues for more specific localizations of the sensitization, could not lead to a precise experimental model and finally did not lead to guidance for specific treatment of tension-type headache.
One of the most exciting developments in pain research over the past decades has been the recognition that the response generated by the somatosensory system to a defined input is not fixed or static. In particular, the increased knowledge on central sensitization, i.e. increased excitability of neurons in the central nervous system, has been a major breakthrough in the understanding of chronic pain. In 1983 Woolf and colleagues (Woolf 1983) demonstrated for the first time that a prolonged noxious input from the periphery is capable of sensitizing spinal dorsal horn neurons. It has later been demonstrated that the central sensitization is induced by repetitive C-fiber, but not A-fiber, input (Yaksh and Malmberg 1994). In the sensitized state, a low-intensity stimulus can generate pain, the phenomenon of allodynia. The low-intensity stimulus is mediated via low-threshold afferents, A-b-fibers, which do not normally mediate pain, and it has been suggested that the major cause of increased pain sensitivity in the chronic pain condition is an abnormal response to A-b-sensory input (Woolf and Doubell 1994). The original findings by Woolf and colleagues on spinal dorsal horn sensitization have later been confirmed by numerous independent laboratories (Mense 1993), and a similar sensitization of trigeminal brainstem nociceptive neurons following stimulation of craniofacial muscle afferents has been reported by Hu et al. (Hu et al. 1992). While central sensitization may be of relevance in many different chronic pain conditions it is particular likely in muscle pain, because input from muscle nociceptors is more effective in inducing prolonged changes in the behavior of dorsal horn neurons than is input from cutaneous nociceptors (Wall and Woolf 1984).
The inventors of the present invention have discovered that the central nervous system is sensitized in patients suffering from increased myofascial pain in connection with tension-type headache because of prolonged nociceptive input from myofascial tissues. The present inventors were then able to devise, for the first time, an effective treatment of tension-type headache, which comprises interacting with neuronal transmission connected with nociception so as to prevent or reduce central sensitization.
A better understanding of the principle of the invention can be derived from the detailed description of the scientific background in the scientific section below.
Pain physiology and pain pharmacology have mostly been elucidated in animal studies. There are, however, no animal models with any proven validity in tension-type headache. Furthermore, these animal experimental studies are done in anaesthetized animals while the sensation of pain by definition can only occur in awake beings. Most of the experiments are also of an acute nature stimulating for milliseconds and recording responses for seconds, minutes or hours and are therefore of uncertain validity for chronic tension-type headache. Finally, only few studies have been done on myofascial tissues projecting via the trigeminal nerve while the huge body of knowledge otherwise available deals with mechanisms of the spinal cord. None of the experimental animal studies mention any form of headache, neither do they suggest that the results of these studies may be utilized for the treatment of tension-type headache. However, after the crucial findings leading to the present invention were made, it is clear that the implications of the findings in relation to general pain physiology can also be utilized in relation to tension-type headache.
With respect to medicinal treatment of tension-type headache, the prior art mentions a variety of substances. The substance Flupirtin (ethyl 2-amino-6-(4-fluorobenylamino)-3-pyridylcarbamate), which is suggested to work as an NMDA glutamate receptor antagonist (Schwartz et al. 1981), has been suggested for use in the treatment of chronic or episodic tension-type headache, as disclosed in EP 0 659 410 A2, and according to Wxc3x6rz et al., 1996, it has shown positive effects. However, in these documents the substance is described as a muscle relaxant, and the mechanism by which it is proposed to exert its effect in the treatment of various conditions, including tension-type headache, is by lowering muscle tension. Thus, as opposed to the present inventors, the prior art understands and explains tension-type headache as a condition directly and primarily caused by muscle tension. WO 96/32386 concerns arylglycinamide derivatives which are antagonists of neurokinins, and these compounds are broadly claimed for use in the treatment of a wide variety of conditions in which neurokinins are supposed to be implicated. Tension-type headache is mentioned as such a condition, but there is no indication of what the mechanism of neurokinin involvement might be. For all the above-mentioned prior art documents, it can be said that the concept of central sensitization in relation to tension-type headache, as introduced by the present inventors, is not described or contemplated at all. Indeed, the prior art does not appear to be concerned with the underlying physiological mechanisms of tension-type headache, but seems to reflect presently held notions of pain physiology in general.
In connection with the present invention, the tern xe2x80x9carylglycinamide derivative as disclosed in WO 96/32386xe2x80x9d means a compound as defined in any of claims 1-17 of WO 96/32386. As appears from the claims herein, these arylglycinamide derivatives are excluded from the definitions of all aspects of the present invention. The excluded arylglycinamide derivatives of claims 1-17 of WO 96/32386 are all comprised by the definition given in claim 1 of WO 96/32386. Thus, whenever reference is made to an xe2x80x9carylglycinamide derivative as disclosed in WO 96/32386xe2x80x9d, this means an arylglycinamide derivative covered by the definition of claim 1 of WO 96/32386, that is:
Arylglycinamide derivatives of the general formula I 
and their pharmaceutically acceptable salts, in which
Ar is unsubstituted or 1-5 times substituted phenyl, or unsubstituted or 1 or 2 times substituted naphtyl [the substituents of phenyl and naphthyl independently of each other being halogen (F, Cl, Br, J), OH, (C1-C4)alkyl, Oxe2x80x94(C1-C4)alkyl, CF3, OCF3 or NR9R10 (wherein R9 and R10 independently of each other a are H, methyl or acetyl)], or Ar is phenyl substituted with xe2x80x94OCH2Oxe2x80x94 or xe2x80x94O(CH2)2Oxe2x80x94;
R1 and R2 together with the N to which they are bound form a ring of the formula 
wherein p is 2 or 3,
X means oxygen, N(CH2)nR6 or CR7R8, wherein
n is 0, 1 or 2,
R6 is (C3-C7)cycloalkyl, phenyl or naphthyl, each phenyl optionally being 1-3 times substituted with halogen (F, Cl, Br, J), (C1-C4)alkyl, Oxe2x80x94(C1-C4)alkyl, CF3, OCF3 or NR15R16 (wherein R15 and R16 independently of each other are H, methyl or acetyl);
R7 and R8 have one of the following meanings
a) when R3 is unsubstituted or substituted phenyl, then R7 and R8 are H,
b) when is R8 is H, xe2x80x94CONH2, xe2x80x94NHC(O)CH3, xe2x80x94N(CH3)C(O)CH3, CN, 
or xe2x80x94C(O)N((C1-C3)alkyl)2,
then R7 is phenyl, phenyl substituted with 1-3 substituents [wherein the substituents independently from each other are halogen (F, Cl, Br, J), (C1-C4)alkyl, Oxe2x80x94(C1-C4)alkyl, CF3 or OCF3], piperidinyl, 1-methylpiperidinyl, 
xe2x80x83or
c) R7 and R8 together form the moiety 
R3 is H, (C1-C4)alkyl, unsubstituted or 1-3 times substituted phenyl, wherein the substituents independently of each other are halogen, (C1-C4)alkyl, Oxe2x80x94(C1-C4)alkyl, CF3, OCF3 or NR17R18 (wherein R17 and R18 independently of each other are H, methyl or acetyl);
R4 is phenyl(C1-C4)alkyl or naphthyl(C1-C4)alkyl, wherein phenyl may be substituted with 1-3 substituents: which substituents independently of each other are halogen (F, Cl, Br, J), (C1-C4)alkyl, Oxe2x80x94(C1-C4)alkyl, CF3, OCF3 or NR19R20 (wherein R19 and R20 independently of each other are H, methyl or ethyl,
and
R5 is H, (C1-C4)alkyl, (C3-C6)cycloalkyl, CH2COOH, xe2x80x94CH2C(O)NH2, xe2x80x94OH or phenyl (C1-C4)alkyl.
As discussed, precious studies in tension-type headache have in general terms indicated that there may be sensitization of muscle and nociceptive afferents and also in a non-specific way have suggested some kind of central sensitization. Whether one or the other kind of sensitization is the more important or whether indeed they both co-exist has not been clear. Recent series of experiments by the present inventors have now clearly shown that tension-type headache is indeed much more complicated than previously anticipated; thus neither the phenomenon of peripheral sensitization nor that of unspecific central sensitization does in isolation explain the condition. The studies of the present inventors have demonstrated that mechanical force due to contraction of chewing muscles may induce peripheral sensitization in chewing muscles and that this peripheral sensitization is an important factor which may or may not induce headache (Jensen and Olesen 1996). Whether this happens depends on the response of the central nervous system. Further experiments have shown for the first time that a qualitatively altered pain perception related to sensitization of second order nociceptive neurons is chronically present in subjects with tension-type headache (Bendtsen et al. 1996c). This is believed to be far the most important abnormality in tension-type headache. Thirdly, recent studies by the present inventors have demonstrated that in addition to sensitization of second order nociceptive neurons, there is also a component of a more unspecific sensitization of pain pathways at higher levels of the central nervous system (Bendtsen et al. 1996b). While sensitization of second order neurons is believed to be segmental (located only in those segments of the spinal cord/trigeminal nucleus which receive afferents from myofascial tissues), the sensitization of higher centers is of a general nature and results in increased pain sensitivity all over the body. It is anticipated that the sensitization of supraspinal neurons is a consequence of the considerably increased nociceptive input to these neurons (Lamour et al. 1983) because of the sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thus, the generalized pain hypersensitivity reflects the sensitization of second order neurons. Moreover, a recent study (Ashina et al. 1998a, Example 4 herein) by the inventors has demonstrated that the nitric oxide synthase (NOS) inhibitor, L-NG methyl arginine hydrochloride (L-NMMA), is effective in the treatment of patients with chronic tension-type headache. Since NOS inhibitors reduce spinal dorsal horn sensitization induced by continues painful input from the periphery (Mao et al. 1997) this study provides additional evidence for central sensitization at the level of the spinal dorsal horn/trigeminal nucleus in patients with tension-type headache. Another recent study (Example 8 herein) by the inventors has demonstrated that L-NMMA reduces muscle hardness in patients with tension-type headache. Increased muscle hardness is anticipated to reflect central sensitization, since it is known that central sensitization may increase the drive to motor neurons both at the supraspinal and at the segmental level (Woolf 1983), resulting in increased muscle activity and thereby in increased muscle hardness. This study, therefore, also points towards central sensitization in tension-type headache. Finally, the present inventors have recently demonstrated that experimental tooth clenching induces increased tenderness of masticatory muscles in patients with tension-type headache and that the increased tenderness precedes the induced headache by several hours (Jensen and Olesen 1996), and that the central nervous system is sensitized only in patients with tender pericranial muscles and not in patients without tender pericranial muscles (Jensen et al. 1998). Together, these studies demonstrate that the central nervous system is sensitized at the level of the spinal dorsal horn/trigeminal nucleus in patients with tension-type headache because of prolonged nociceptive input from myofascial tissues. On the basis of the combined findings of the inventors, a novel and rather complex model of the mechanisms of tension-type headache has been developed, as depicted in FIG. 1. In the following the model is described in details and its significant implications for devising successful future drug treatment of tension-type headache are discussed.
The model is illustrated in FIG. 1, in which the abbreviations have the following meaning:
The main circuitry in FIG. 1 is the following:
Voluntary muscle activity is initiated by the supplementary motor area. This activates the motor cortex which again activates the motor nucleus of the trigeminal nerve and anterior horn cells of the C2 and C3 segments of the spinal cord causing contraction of chewing and neck muscles. Simultaneously with the activation of motor cortex, the supplementary motor area also activates the antinociceptive system. Therefore normal muscle activity, even when vigorous, is not normally perceived as painful. Another way of activating the motor pathways is via the limbic system which is concerned with emotions. When this system is activated, as in states of anxiety and stress, it is envisaged that the motor cortex and the pain facilitator system are activated simultaneously. Thus, emotionally induced involuntary muscle contraction usually induces myofascial tenderness and pain. Both voluntary and emotionally triggered muscle contraction via mechanical stress and perhaps neurogenic inflammation increase afferent input from myofascial tissues via C-fibers, A-d-fibers and A-b-fibers. C-fiber input is responsible for slow pain and, when prolonged, causes the so-called wind-up phenomenon in second order neurons located in the nucleus of the trigeminal tract and in segments C2 and C3 of the dorsal horn of the spinal cord. Wind-up is associated with increased sensitivity of second order neurons and an increase of their receptive fields. Furthermore, input via A-b-fibers becomes painful which is called allodynia. Input from the periphery in a state of wind-up causes a more intense pain than normally. With repeated or chronic micro traumatic or inflammatory reactions in myofascial tissues peripheral nociceptores, primarily projecting via C-fibers, become sensitized. Substances involved in peripheral sensitization include the potassium ion, bradykinin, histamine, ATP, neurotrophins and possibly other growth factors (Meyer et al. 1994).
How does repetitive C-fiber input to the spinal dorsal horn result in abnormal responses to normal Ab-fiber inputs, i.e. in central sensitization? The most likely answer is that C-fiber released neurotransmitters increase the excitability of dorsal horn neurons, so that previously ineffective Ab-fiber inputs to nociceptive dorsal horn neurons become effective (Woolf and. Thompson 1991). Several neurotransmitters are known to be involved in nociceptive transmission from C-fiber afferents to second order neurons in the spinal dorsal horn. These neurotransmitters can largely be divided into gases, into peptides, which are chains of amino acids, or into excitatory or inhibitory amino acids. Which are chemically single amino acids and into excitatory or inhibitory amines.
The freely diffusible gas nitric oxide (NO) is probably released from C-fibers and acts after binding to the enzyme guanylate cyclase in postsynaptic neurons. However, even though NO is considered of major importance in central sensitization, its exact role as a neurotransmitter is not yet clarified (Meller and Gebhart 1993).
Neurokinins are a family of related peptides, including substance P, neurokinin A, neurokinin B and bradykinin which are known to be released from C-fibers. Currently there are three known subclasses of receptors for these peptides: neurokinin-1, (NK1) NK2 and NK3 receptors.
PACAP is expressed in abundant amounts in dorsal horn neurons and is believed to play a significant role in pain transmission or the modulation of pain transmission.
The exact role of this peptide in pain transmission is not known because of lack of selective receptor antagonists. However, CGRP probably protracts the breakdown of substance P in the synaptic cleft, thereby adding to the level of excitability of the spinal cord (Dickenson 1996).
Several other peptides such as somatostatin, neuropeptide Y and galanin ray be important, but their exact role in central sensitization is not yet known.
It now appears that the excitatory amino acid glutamate plays a dominant role in the development of central sensitization. Glutamate is used by most neurons in the brain and spinal cord as their major excitatory transmitter. The actions of glutamate are mediated by 4 different receptor classes: the N-methyl-D-aspartate (NMDA), the a-amino-3-hydroxy-5-methyl-4-isoxazolyl-propionic acid (AMPA), the kainate receptors, and the metabotropic receptors. Of these receptors, especially the NMDA receptors are considered to be of crucial importance in central sensitization (Coderre et al. 1993).
The central terminals of primary afferent fibers do express adenosine receptors (Levine and Taiwo 1994). Via these receptors, adenosine can inhibit voltage-gated calcium channels via activation of a G-protein resulting in an inhibition of transmitter release from the primary afferent neuron (Rang et al. 1994). Adenosine agonists may also act to inhibit the firing of wide-dynamic neurons, probably through an increase in potassium conductance. Furthermore, adenosine has been reported to block the release of glutamate (Yaksh and Malmberg 1994). In support of these findings intrathecal adenosine has been shown to increase the nociceptive threshold (Yaksh and Malmberg 1994). Adenosine does also play a role in the peripheral tissues. In the primary afferent nociceptor adenosine acting at the A1-receptor inhibit hyperalgesia, while adenosine acting at the A2-receptor produces hyperalgesia via elevation of intracellular cAMP Levine and Taiwo 1994).
GABA is an important inhibitory transmitter in the central nervous system, and it has been suggested that the encoding of low-threshold mechanical stimuli as innocuous depends completely upon the presence of a tonic activation of intrinsic glycine and/or GABAergic neurons (Yaksh and Malmberg 1994). Furthermore, it has been demonstrated that the administration of GABA antagonists can produce allodynia (Woolf 1994). GABAB agonists may act to inhibit the firing of wide-dynamic neurons, probably through an increase in potassium conductance (Yaksh and Malmberg 1994) and GABA may also reduce the amount of transmitter release from the central terminals of primary afferent fibers by opening of chloride channels (Rang et al. 1994).
5-HT is a very important transmitter in the modulation of pain. While 5-HT has both analgesic and algesic properties, it acts mainly as an inhibitory pain transmitter in the central nervous system (Roberts 1992). Thus, when 5-HT is applied directly to the spinal cord, it produces analgesia (Fields and Basbaum 1994). The antinociceptive effects of 5-HT are mediated via many different 5-HT receptor subtypes. Thus, it is known that both the 5-HT1 and 5-HT2 and 5-HT3 receptors are involved in antinociception (Fields and Basbaum 1994).
Like 5-HT, also norepinephrine (NE) plays an important role as an endogenous antinociceptive transmitter. In general, noradrenergic controls are mediated at the spinal level by the action at the a-2-adrenergic receptor (Fields and Basbaum 1994). The a-2-agonist clonidine has been shown to block the release of transmitters and peptides in primary afferent terminals by presynaptic action, and it is most likely that the analgesic effects of the tricyclic antidepressants partly depend on their inhibition of norepinephrine re-uptake (Boivie 1994).
Why are the NMDA receptors considered so important? The actions of many receptors on neuronal excitability are via opening or closing of ion channels. The ion channel for the NMDA receptors allows vast amounts of calcium into the neuron, so much that the resultant increase in excitability exceeds that produced by all other receptors (Dickenson 1996). The increase in intracellular calcium initiates a cascade of biochemical events. Thus, calcium activates a calmodulin-sensitive site on NO synthase, which results in the production of NO. NO may thereafter act via at least three different mechanisms: 1) it may act in the neuron where it is produced, e.g. by increasing cyclic guanylate mono phososphate (cGMP) levels which again will activate protein kinases or by inducing the expression of immediate early genes. The protein kinases and the protein products of immediate early genes may then act as third messengers and control the expression of other genes involved in the synthesis of growth factors, channel proteins, peptides and enzymes; 2) it may act as a retrograde transmitter by diffusion to the presynaptic neuron where it modulates excitability and enhances synaptic connections; and 3) it may diffuse to adjacent neurons, e.g. interneurons (Meller and Gebhart 1993). Another important result of increased intracellular calcium is the activation of phospholipase A2, leading to increases in intracellular arachidonic acid and the subsequent formation of cyclooxygenase and lipooxygenase products. Prostaglandins have been shown to increase calcium conductance on dorsal root ganglion cells and to increase the secretion of primary afferent peptides such as substance P (Yaksh and Malmberg 1994). Activation of the NMDA receptors thus has dramatic consequences and the receptors are therefore usually blocked, such that they do not participate in normal transmission. This channel block, which is mediated by physiological levels of Mg2xe2x88x92 ions, can only be removed by sufficient repeated depolarization of the membrane. It is suspected that the neurokinins co-released with glutamate from C-fibers contribute to the removal of Mg2+ ions. This important action of the neurokinins is probably mediated via NK1 and NK2 receptors (Dickenson 1996). Also the protein kinases activated by NO will feed back on the NMDA receptors, causing phosphorylation and partial removal of the Mg2+ channel blockade (Woolf 1996). Other glutamate receptors are probably also involved in central sensitization, but the exact mechanisms are not yet known.
The increased excitability of neurons in the spinal dorsal horn/trigeminal nucleus has dramatic consequences for the pain perception in the individual patient. In the sensitized state, pain can be generated by low-threshold Ab-fibers (allodynia) (Torebjxc3x6rk, et al. 1992), the response to activation of high-threshold afferents is exaggerated (hyperalgesia) (Woolf 1994), and since the receptive field of the dorsal horn neuron is increased, the central sensitization will also be manifest as a spread of hypersensitivity to uninjured sites (secondary hyperalgesia) (Torebjxc3x6rk et al. 1992).
When noxious input is received in the nucleus of the trigeminal tract, its further transmission to the thalamus and sensory cortex depends on the intensity of the input and on the balance between pain inhibiting and pain facilitating descending systems originating from the brain stem. When the pain inhibiting system is activated, it decreases the likelihood that incoming stimuli are being transmitted to the thalamus and, alternatively, when the facilitatory system is activated, it increases the likelihood of this event. From the thalamus, nociception is projected further to the sensory cortex. Via unknown mechanisms pain causes a reflex increase in muscle tone. It is envisaged that this response to pain is mediated via the limbic system because pain and anxiety are closely interrelated. There is also a cross-talk between nociception and motor activity at the level of the trigeminal nucleus/spinal cord. Finally, pain activates the sympathetic system causing release of noradrenaline. This again is responsible for an increased pain sensation, so-called sympathetically aggravated or maintained pain.
The progression of episodic tension-type headache into chronic tension-type headache often takes several years and happens only in a minority of episodic tension-tape headache sufferers. A genetic disposition (Østergaard et al. 1996) as well as several environmental factors seem to be involved in the development of chronicity. Despite the fact that the progression is continuous, it is best illustrated by a number of scenarios.
Scenario 1: Mild and moderate muscle contraction in normals. Voluntary muscle contraction in relation to normal functions such as chewing or head holding is initiated from the supplementary motor cortex. This is probably associated with only a minor increase in nociception from myofascial tissues and no wind-up in non-headache sufferers. Simultaneously the antinociceptive system is activated such that no sensation of pain occurs.
Scenario 2: Forceful and/or long-lasting muscle activity, in normals. With particularly vigorous muscle activity and especially when it is very protracted, the strain on myofascial tissues may be such that nociception is rather marked and tenderness and local pain may occur, but it is rapidly controlled by local reparative mechanisms in myofascial tissues and a continuously active antinociceptive system. Tenderness without spontaneous pain on the day after exercise may be a result of this balance or may be a purely local phenomenon.
Scenario 3: Involuntary muscle activity induced by the limbic system in normals. In contrast to activation initiated by the supplementary motor area, muscle contraction initiated by the limbic system is not associated with an increased antinociceptive activity. On the contrary it is proposed to be associated with increased activity in the pain facilitatory system. An alternative is a decrease in the activity of the antinociceptive system, but this is unlikely because this system is normally not tonically active. Limbic initiated muscle activity therefore causes pain even with moderate degrees of contraction and also with relatively short-lasting contractions. However, in normals the drive from the limbic system is short lasting and so are the mild changes in myofascial tissues induced by the motor activity. The headache is therefore self limiting.
Scenario 4: Voluntary contraction in patients with severe episodicxe2x80x94and chronic but not daily tension-type headache. In most of these individuals voluntary muscle activity will be painful. In part this is due to permanent sensitization of second order neurons in the nucleus of the trigeminal tract, in part it is due to the fact (Jensen and Olesen 1996) that the antinociceptive system is not activated as normally. Contraction therefore aggravates tenderness and causes pain from the myofascial structures (Jensen and Olesen 1996) The process of reverting the system back to normal may be more or less effective. This variable duration of the initiating stimulus accounts for the variable duration of the headache.
Scenario 5: Severe (daily) chronic tension-type headache.
In severe chronic tension-type headache there is a state of chronic sensitization in myofascial tissues and in central pain pathways both at the second order neurons and at higher centers. There is a minor constant elevation of EMG signal from cranial muscles. In addition, the most severe cases also have a more diffuse sensitization revealed in decreased pain thresholds throughout the body (Bendtsen et al. 1996b). Chronically increased muscle activity maintains a state of chronic peripheral sensitization which again maintains a state of chronic sensitization in the second order neurons in the nucleus of the trigeminal tract (Bendtsen et al. 1996c). This causes steady inflow of nociceptive signals to the thalamus and the perception of chronic pain by the sensory cortex. This again activates the limbic system and stimulates tonic involuntary muscle activity. In this situation of chronic pain there is probably also activation of the sympathetic nervous system adding a component of sympathetically mediated pain to the whole picture. On top of this chronic situation of sustained pain, it is easy to see how additional strain would result in increased and prolonged pain. A further increase in muscle activity would for instance in the sensitized peripheral myofascial tissues lead to a stronger than normal nociceptive input to the already sensitized nucleus of the trigeminal tract which would project to already sensitized hemispheric pain centers. A vicious circle has been set up and it may become permanent due to changes in gene transcription and consequent structural changes in neurons aid synapses.
Previous treatments have primarily been directed towards reducing muscle contraction i.e. biofeedback treatment, physiotherapy, dental treatment, exercises and muscle relaxants. All of these treatments have had limited or no success. It follows from the model according to the present inventors that therapeutic intervention should be directed primarily towards the afferent system and above all against sensitization of second order neurons in the nucleus of the trigeminal tract and upper cervical segments. Furthermore, it follows that while intervention using peripherally acting analgesics or other measures which reduce peripheral nociceptive input is sufficient in episodic tension-type headache, this is not so for severe episodic and chronic tension-type headache, where sensitization of second order neurons occurs. In these patients, desensitization of these neurons should be the major target for drug intervention. It may, however, be difficult to desensitize these neurons in face of an ongoing vigorous input from the periphery. Therefore, drugs which reduce peripheral sensitization may be needed in addition to the drugs which desensitize second order nociceptive neurons, or drugs working at both levels may be needed. Preferably, treatment should be given early enough to prevent sensitization of second order neurons. Alternatively, if marked sensitization at the cortical level occurs, the individual being hypersensitive to painful stimuli all over the body, it may not be enough to intervene against the sensitization of second order neurons. For such patients intervention against cortical sensitization is recommended as an additional measure.
According to the present invention, several means of intervening against tension-type headache can be envisaged, depending on the level according to the above, at which the intervention is aimed. In either case, be it in the periphery, the second order neurons of the sensory trigeminal nucleus or the cortex, the intervention must target the transmission of nerve impulses. A number of different transmitter substances are involved in this transmission at each level. Thus, the invention, in some of its aspects, relate to the following therapeutic principles in tension-type headache of the chronic type and of the severe episodic type defined as having headaches ten or more days per month:
Administration of agents or drugs (in the present specification and claims, the terms agent and drug are used as interchangeable) which prevent or reduce sensitization of second order nociceptive neurons located in the nucleus of the descending tract of the trigeminal nerve and in the C2 and C3 segments of the dorsal cervical horn of the spinal cord. There are several known types of assays indicating the capability of an agent to prevent or reduce central sensitization. In the following, 13 such assays are described.
Administration of agents or drugs which reduce supraspinal pain sensitization to a normal level. These are agents or drugs which normalize the response of pressure pain thresholds in the temporal region to tooth clenching and drugs which normalize pain thresholds in hand.
Administration of agents or drugs which reduce peripheral sensitization defined as agents or drugs which prevent the development of abnormal tenderness due to tooth clenching.
Administration of agents or drugs which normalize the pain response to intra muscular infusion of bradykinin, 5-HT, histamine, prostaglandines and/or nitroglycerine.
Administration of agents or drugs which normalize local pressure pain threshold over myofascial tissues of the head.
Administration of agents or drugs which have more than one of the above effects.
Administration of agents or drugs which in a panel of test patients with tension-type headache have one of the above effects described one by one.
When targeting the transmission of nerve impulses according to the invented model, it is preferred to interact with the following substances relating to neurotransmission in connection with pain:
Glutamate
Substance P
Nitric oxide
GABA
It is particularly preferred to:
Antagonize the effect of glutamic acid
Antagonize the effect of substance P
Antagonize the effect of nitric oxide
Stimulate the effect of GABA.
More specifically, it is preferred to use:
NMDA receptor antagonists
Inhibitors of neuronal nitric oxide synthase (NOS)
GABA A and GABA B receptor agonists
In order to counteract central sensitization of second order neurons of the sensory trigeminal nucleus/dorsal horn, it will be advantageous to cause a decrease in neuronal transmission involving the pathways utilizing e.g. the transmitter substances glutamate, nitric oxide, and the neurokinins (substance P, bradykinin, neurokinin A, neurokinin B). Also, it will be of interest to counteract the action of second messengers such as guanylate cyclase, cGMP as well as any further steps in the action of cGMP in second order sensory neurons receiving nociceptive input from the head and neck.
In order to prevent the occurrence of central sensitization of second order neurons of the sensory trigeminal nucleus/dorsal horn, it will be advantageous to normalize neuronal transmission in the peripheral and/or central nervous system involving transmitter substances such as glutamate, GABA, adenosine, nitric oxide, the neurokinins (substance P, bradykinin, neurokinin A, neurokinin B), neurotrophins and histamine. While it might have seemed advantageous to use 5-HT1D receptor agonists because they stabilize presynaptic nociceptive terminals, studies by the inventors have shown that a compound of this class (sumatriptan) is not effective to a clinically relevant extent in tension-type headache although it is highly effective in migraine (Brennum et al. 1992, 1996). Counteracting excitatory 5-HT receptors, such as 5-HT2 and 5-HT3 localized on second order neurons, however, are contemplated to be effective in the treatment of tension-type headache in accordance with the present invention.
On the basis of their experimental discoveries and analyses, the present inventors have devised, for the first time, a strategy for the treatment or prevention of tension type headache. Up to now, there has not been any effective treatment available for tension type headache, which has been a very serious problem in view of the very high prevalence of tension-type headache.
The present invention relates to a method of treatment or prevention of tension-type headache in a person in need of such treatment, the method comprising administering an amount of an agent effective to interact with neuronal transmission connected with pain perception so as to prevent or reduce central sensitization.
The attainment of prevention or reduction of central sensitization can be demonstrated by one of the following assays:
1) Normalization of a pathological qualitatively altered stimulus-response function. The attainment of a normalization of a qualitatively altered stimulus-response function in connection with nociception (Bendtsen et al. 1996c, Example 1) can be demonstrated by palpation of the trapezius muscle and recording of the degree of pain corresponding to the intensity of palpation (Bendtsen et al. 1994). When a curve representing the stimulus/response function in connection with nociception has changed in shape from being substantially linear in a normal representation to being substantially linear in a double logarithmic representation, a normalization of the qualitatively altered stimulus/response function has been obtained. In the present context, an agent which normalizes a qualitatively altered stimulus-response function in connection with nociception is an agent which, when administered to a group of at least 20 patients suffering from tension-type headache, will cause the curve representing the stimulus/response function in connection with nociception to become substantially linear when represented double logarithmically in at least 10 of the patients. Preferably, the agent so defined has such an effect in at least 12 of the patients. More preferably, the agent so defined has such an effect in at least 14 of the patients.
2) Normalization of a pathological abnormally low pain threshold. The attainment of a normalization of an abnormally low pain threshold can be demonstrated by the measurement of the pressure pain threshold in the extremities or in the pericranial region with an electronic pressure algometer or by the measurement of the electrical pain threshold with a constant current stimulator as previously described (Bendtsen et al. 1996a). When the pain threshold has changed from being significantly lower in a group of patients with tension-type headache than in a group of healthy controls to be not significantly different between the two groups, a normalization of the abnormally low pain threshold has been obtained. In the present context an agent which normalizes an abnormally low pain threshold is an agent which, when administered to a group of at least 10 patients suffering from tension-type headache, will change the pain threshold from being significantly lower than that in a group of healthy controls to be not significantly different between the two groups.
3) Reduction of a pathological pericranial muscle hardness. The attainment of reduction of pericranial muscle hardness can be demonstrated by the measurement of hardness in the pericranial muscles with a hardness meter as previously described (Ashina et al. 1998a), when the muscle hardness is reduced significantly more following the administration of a given agent than following the administration of placebo, a reduction of muscle hardness has been obtained. In the present context, an agent which reduces pericranial muscle hardness is an agent which, when administered to a group of at least 10 patients suffering from tension-type headache, will reduce pericranial muscle hardness significantly more than placebo. Such a reduction will typically be at least 10%. Preferably the reduction will be at least 20%. More preferably the reduction will be at least 30%.
4) Reduction of a pathological increased pericranial myofascial tenderness. The attainment of reduction of increased pericranial myofascial tenderness can be demonstrated by the measurement of the tenderness in the pericranial region using the Total Tenderness Scoring system as previously described (Bendtsen et al. 1995). Myofascial tenderness is considered to be increased when the Total Tenderness Score or the Local Tenderness Score in the pericranial region is above the 75% percentile of the Total Tenderness Score or the Local Tenderness Score in a group of healthy controls (Jensen and Rasmussen 1996). In the present context, an agent which reduces increased pericranial myofascial tenderness is an agent which, when administered to a group of at least 10 patients suffering from tension-type headache, will reduce the Total Tenderness Score or the Local Tenderness Score in the pericranial region by at least 10% compared with the administration of placebo. Preferably, the agent so defined will reduce the Total Tenderness Score or the Local Tenderness Score in the pericranial region by at least 20% compared with the administration of placebo. More preferably, the agent so defined will reduce the Total Tenderness Score or the Local Tenderness Score in the pericranial region by at least 30% compared with the administration of placebo.
5) Prevention or reduction of pain, tenderness or hardness in pericranial muscles, or prevention or normalization of a qualitatively altered stimulus-response function or a reduced pain threshold induced by experimental tonic muscle contraction. The attainment of prevention or reduction of pain, tenderness or hardness, or prevention or normalization of a qualitatively altered stimulus-response function or a reduced pain threshold can be demonstrated as described in assays 1-4 above. Experimental tonic muscle contraction can be obtained by clenching of the molar teeth for 30 minutes at 10% of the individual subject""s maximal voluntary contraction measured from electromyographic recordings of the activity in the temporal or masseter muscles as previously described (Jensen and Olesen 1996). In the present context, an agent which prevents or reduces pain, tenderness or hardness, or prevents or normalizes a qualitatively altered stimulus-response function or a reduced pain threshold induced by experimental tonic muscle contraction is an agent which, when administered to a group of at least 10 human subjects, will prevent or reduce pain, tenderness or hardness, or prevent or normalize a qualitatively altered stimulus-response function or a reduced pain threshold induced by experimental tonic muscle contraction to a significantly higher degree than placebo.
6) Prevention or reduction of pain, tenderness or hardness in pericranial muscle, or prevention or normalization of a qualitatively altered stimulus-response junction or a reduced pain threshold induced by intra muscular infusion of algogenic substances. The attainment of prevention or reduction of pain, tenderness or hardness, or prevention or normalization of a qualitatively altered stimulus-response function or a reduced pain threshold can be demonstrated as described in assays 1-4 above. Intra muscular infusion of algogenic substances can be performed by the use of a 0.4 mm needle as previously described (Jensen et al. 1990). Algogenic substances such as bradykinin, serotonin, histamine, adenosine-tri-phosphate, prostaglandines, capsaicin, hypertonic saline, potassium, nitroglycerine or combinations hereof can be used. The algogenic substances can be injected either as a single bolus injection (Jensen et al. 1990) or as a prolonged infusion (Zhang et al. 1993). In the present context, an agent which prevents or reduces pain, tenderness or hardness, or prevents or normalizes a qualitatively altered stimulus-response function or a reduced pain threshold induced by intra muscular infusion of algogenic substances is an agent which, when administered to a group of at least 10 human subjects, will prevent or reduce pain, tenderness or hardness, or prevent or normalize a qualitatively altered stimulus-response function or a reduced pain threshold induced by intra muscular infusion of algogenic substances to a significantly higher degree than placebo.
7) Prevention or reduction of pain, tenderness or hardness in pericranial muscle, or prevention or normalization of a qualitatively altered stimulus-response function or a reduced pain threshold induced by stimulation of nociceptive afferents in myofascial tissues. The attainment of prevention or reduction of pain, tenderness or hardness, or prevention or normalization of a qualitatively altered stimulus-response function or a reduced pain threshold can be demonstrated as described in assays 1-4 above. Stimulation of nociceptive afferents in myofascial tissues can be obtained by methods such as eccentric muscle contraction (Howell et al. 1993), prolonged static muscle contraction, repeated monotonous muscle work, ischemic muscle exercise (Myers and McCall Jr 1983), electrical stimulation via needle electrodes inserted into the muscles (Vecchiet et al. 1988) or mechanical pressure applied to the muscles. In the present context, a substance which prevents or reduces pain, tenderness or hardness, or prevents or normalizes a qualitatively altered stimulus-response function or a reduced pain threshold induced by stimulation of nociceptive afferents in myofascial tissues is a substance which, when administered to a group of at least 10 human subjects, will prevent or reduce pain, tenderness or hardness, or prevent or normalize a qualitatively altered stimulus-response function or a reduced pain threshold induced by stimulation of nociceptive afferents in myofascial tissues to a significantly higher degree than placebo.
8) Prevention or reduction of secondary allodynia or secondary hyperalgesia induced by stimulation of nociceptive afferents in myofascial tissues. The attainment of prevention or reduction of secondary allodynia or secondary hyperalgesia can be demonstrated by measuring pain sensitivity in the unaffected tissue area that surrounds an area in which nociceptive afferents are stimulated (Magerl et al. 1998). Pain sensitivity can be measured by visual analogue scale recording of the pain intensity evoked by stimuli such as mechanical pressures applied by an electronic pressure algometer, manual palpation or pressure-controlled palpation (Bendtsen et al. 1995; Bendtsen et al. 1996a), punctuate mechanical stimuli applied by von Frey hairs (Magerl et al. 1998), light touch stimuli applied by a soft cotton wisp (Magerl et al. 1998), thermal stimuli applied by the Marstock thermotest (Nxc3x8rregaard et al. 1997) or electrical stimuli applied by surface electrodes (Bendtsen et al. 1996a) or intra muscular needle electrodes (Vecchiet et al. 1988) or by measuring the nociceptive flexion reflex (Willer et al. 1984). Stimulation of nociceptive afferents in myofascial tissues can be obtained as described in assays 5-7 above. In the present context, an agent which prevents or reduces secondary allodynia or secondary hyperalgesia induced by stimulation of nociceptive afferents in myofascial tissues is an agent which, when administered to a group of at least 10 human subjects, will prevent or reduce secondary allodynia or secondary hyperalgesia induced by stimulation of nociceptive afferents in myofascial tissues to a significantly higher degree than placebo.
9) Prevention or reduction of wind-up induced by repetitive stimulation of nociceptive afferents in the pericranial region. The attainment of prevention or reduction of wind-up can be demonstrated by measuring pain sensitivity to repeated stimuli (Magerl et al. 1998), since temporal summation of painful stimuli is regarded as a psychophysical correlate of wind-up (Price et al. 1994). In the present context, wind-up is defined to be present when repeated identical stimuli become increasingly painful (Pedersen et al. 1998). Wind-up can be induced by stimuli such as repeated electrical stimuli, e.g. five stimuli of 1 ms duration with an intensity of 1.4 times the baseline pain threshold delivered at 2 Hz by a constant current stimulator (Pedersen et al. 1998), or as repeated punctuate mechanical stimuli, e.g. five stimuli delivered at 2 Hz with a 256 mN calibrated von Frey hair (Magerl et al. 1998). The evoked pain intensity can be measured using a visual analogue scale. In the present context, an agent which prevents or reduces wind-up induced by stimulation of nociceptive afferents in the pericranial region is an agent which, when administered to a group of at least 10 human subjects, will prevent or reduce wind-up induced by stimulation of nociceptive afferents in the pericranial region to a significantly higher degree than placebo.
10) Prevention or reduction of secondary allodynia or secondary hyperalgesia induced by nociceptive input in an experimental animal model. The degree of secondary allodynia or secondary hyperalgesia can be examined by measuring pain sensitivity in the unaffected tissue area that surrounds an area in which nociceptive afferents are stimulated (Magerl et al. 1998). Pain sensitivity can be measured by recording the response of the animal to well-defined stimuli, e.g. briskly stroking the skin with the blunt point of a pencil (Magerl et al. 1998), mechanical pressures applied by an electronic pressure algometer, manual palpation, pressure-controlled palpation or calibrated von Freys hairs (Hao et al. 1992), electrical stimuli or thermal stimuli (Hao et al. 1992). The response of the animal can be measured by methods such as: a) grading of the behavior of the animal to avoid a given stimulus, e.g. as a score of 0: no response; 1: moderate efforts to avoid the stimulus; and 2: vigorous efforts to escape the stimulus (Hao et al. 1992); b) recording the time required for eliciting a given response of the animal, e.g. withdrawal of an extremity, by a given stimulus (Hao et al. 1992); c) recording the intensity of a stimulus that elicits a given reaction, e.g. vocalization or withdrawal or licking of an extremity (Hao et al. 1992); or d) by a combination of the above-mentioned methods (Hao et al. 1992). The induction of secondary allodynia or secondary hyperalgesia can be performed as described above in assays 6 and 7 or by methods such as the application to the skin of chemical irritants, e.g. mustard oil (Woolf and King 1990), thermal stimuli (Hylden et al. 1989), pinching, subcutaneous or intra muscular injections of complete Freund""s adjuvant (Hylden et al. 1989). In the present context, an agent which prevents or reduces secondary allodynia or secondary hyperalgesia induced by nociceptive input in an experimental animal model is an agent which will prevent or reduce secondary allodynia or secondary hyperalgesia induced by nociceptive input in an experimental animal model to a significantly higher degree than placebo.
11)Prevention or reduction of wind-up induced by repetitive stimulation of nociceptive afferents in as experimental animal model. The degree of wind-up can be examined by measuring pain sensitivity (Magerl et al. 1998) or the activity of second order neurons to repeated stimuli (Woolf and Thompson 1991). In the present context, wind-up is defined to be present when repeated identical stimuli become increasingly painful (Pedersen et al. 1998) or potentiate the responses of second order neurons (Laird et al. 1995). Pain sensitivity in animals can be recorded as described above in assay 10, while the activity of second order neurons can be measured using extra- and intracellular recordings of the activity in these neurons (Woolf and King 1990; Hu et al. 1992). After exposure of the spinal cord via laminectomy, extracellular recordings can be made using glass microelectrodes and intracellular recordings can be made using potassium acetate electrodes (Woolf and King 1990). Wind-up can be induced by stimuli such as those described in assay 10. In the present context, an agent which prevents or reduces wind-up induced by repetitive stimulation of nociceptive afferents in an experimental animal model is an agent which will prevent or reduce wind-up induced by repetitive stimulation of nociceptive afferents in an experimental animal model to a significantly higher degree than placebo.
12) Prevention or reduction of increased receptive field size of second order neurons induced by nociceptive input in an experimental animal model. The receptive field size of second order neurons can be measured using extra- and intracellular recordings of the activity in these neurons (Woolf and King 1990; Hu et al. 1992) as described above in assay 11. The receptive fields can be mapped using stimulation with e.g., calibrated von Frey hairs, blunt probes (Hylden et al. 1989), thermal stimuli (Hylden et al. 1989), serrated forceps or calibrated pinchers applied to the skin (Woolf and King 1990). The induction of increased receptive field size of second order neurons can be performed as described above in assay 10. In the present context, an agent which prevents or reduces increased receptive field size of second order neurons induced by nociceptive input in an experimental animal model is an agent which will prevent or reduce increased receptive field size of second order neurons induced by nociceptive input in an experimental animal model to a significantly higher degree than placebo.
13) Prevention or reduction of increased excitability of the flexion reflex induced by nociceptive input in an experimental animal model. The excitability of the flexion reflex can be examined by measuring the activity in flexor motor neurons elicited by a standard stimulus applied ipsilaterally to the recording of flexor motor neuron activity (Woolf 1983). The examination can, e.g., be performed by extracellular recordings of the activity from flexor alpha motor neurons to the posterior biceps femoris/semitendinosus muscles in the decerebrate rat (Woolf and Thompson 1991). The flexion reflex can, e.g. be elicited by a standard pinch applied to the ipsilateral toes (Woolf and Thompson 1991). The induction of increased excitability of the flexion reflex can be performed as described above in assay 10. In the present context, an agent which prevents or reduces increased excitability of the flexion reflex induced by nociceptive input in an experimental animal model is an agent which will prevent or reduce increased excitability of the flexion reflex induced by nociceptive input in an experimental animal model to a significantly higher degree than placebo.
Prevention or reduction of central sensitization induced by nociceptive input in an experimental animal model. The degree of central sensitization in an experimental animal model can be measured by other methods which are presumed to reflect central sensitization but which are not mentioned in the above described assays 10-13, i.e. measurement of cellular intermediate early genes such as c-fos (Dubner and Ruda 1992). The induction of central sensitization can be performed as described above in assay 10. In the present context, an agent which prevents or reduces central sensitization induced by nociceptive input in an experimental animal model is an agent which gill prevent or reduce central sensitization induced by nociceptive input in an experimental animal model to a significantly higher degree than placebo.
In the present context the term xe2x80x9csignificantly higher degree than placeboxe2x80x9d should be taken to mean statistically significant when the relevant statistical tests are applied to data relating to an effect of an agent according to the invention compared to an effect of placebo in any given assay or test.
The interaction with neuronal transmission connected with pain perception will normally be interaction with neuronal transmission connected with second order nociceptive neurons. This interaction will normally involve prevention of sensitization by way of a reduction of C-fiber input to the second order nociceptive neurons or reversal of an already established sensitization of second order nociceptive neurons.
Interaction with neuronal transmission connected with pain perception can be exerted by increasing inhibitory synaptic stimuli or it can be exerted by decreasing excitatory synaptic stimuli.
By the term xe2x80x9cpalpationxe2x80x9d is meant the act of applying, with the fingers, pressure to the surface of the body for the purpose of determining the amount of pain elicited in the underlying tissue by said pressure intensity.
In the present context, the term xe2x80x9cqualitatively altered stimulus/response functionxe2x80x9d in connection with nociception means that the function describing the amount of pain elicited by a given pressure intensity, sensed by a person being palpated, has changed in shape from being positively accelerating to being substantially linear, of Example 1.
By the term xe2x80x9ctender musclexe2x80x9d is meant a muscle in which pain is elicited by palpation with a clinically relevant pressure.
In the present context, by the term xe2x80x9ccentral sensitizationxe2x80x9d is meant that second order nociceptive neurons residing in the central nervous system are rendered more sensitive than normally to incoming synaptic stimuli. At the occurrence of central sensitization such stimuli will elicit excitation of the said central neurons at stimulation below the normal threshold for excitation; thus, central neurons possess an increased excitability.
In the present context, myofascial pain relates to pain in the myofascial tissue, by which is meant muscular structures, tendons and tendon insertions related to the pericranial and cervical region.
In the context of the present invention second order nociceptive neurons are neurons located in the nucleus of the trigeminal tract and of C2 and C3 segments of medullary dorsal horns, said neurons being involved in the processing of nociceptive stimuli.
By the term xe2x80x9cC-fibersxe2x80x9d is meant a class unmyelinated nociceptive fibers terminating on neurons in the nucleus of the trigeminal tract/dorsal horn of the spinal cord,
The interaction with neuronal transmission connected with pain perception, so as to obtain a substantial prevention or a substantial normalization of an otherwise qualitatively altered stimulus-response function in connection with nociception is preferably performed by administering an effective amount of an agent which prevents or normalizes an otherwise qualitatively altered stimulus-response function in connection with nociception.
In the present context, an agent which prevents or normalizes an otherwise qualitatively altered stimulus-response function in connection with nociception is an agent which, when administered to a group of at least 20 patients suffering from tension type headache as defined above, till cause the curve representing the stimulus/response function in connection with nociception to become substantially linear when represented double logarithmically in at least 10 of the patients. Preferably the agent so defined has such an effect in at least 12 of the patients. More preferably the agent so defined has such an effect in at least 14 of the patients.
A number of substances and classes of substances which interact with neuronal transmission to exert this function are known, confer the detailed discussion thereof in the following.
In accordance with what is explained above, another way of expressing the treatment according to the invention is by reference to pain threshold in connection with chronic contraction of muscle, in particular tooth clenching. Thus, according to this, the invention can be expressed as a method for treatment of tension-type headache in a person in need of such treatment, comprising interacting with neuronal transmission connected with pain perception so as to obtain a substantial increase of an otherwise unresponsive pain threshold in connection with chronic contraction of muscle, in particular tooth clenching.
Again, the interaction is preferably performed by administering an agent which will interact with neuronal transmission in a manner corresponding to what has been described above. The agent can be characterized as a agent which performs positively (as described above), in one or more of the assays described above, such as the stimulus/response function test described above, or as a agent which, in a group of at least 20 patients suffering from tension tape headache as defined above, will cause the effect of tooth clenching to be an increased pain threshold instead of an abnormally low pain threshold in at least 10 of the patients, preferably at least 12 of the patients, more preferably in at least 14 of the patients.
In another aspect, the invention relates to an agent having the properties defined herein for use as a medicament, in particular for the treatment of tension-type headache. This aspect relates to those substances or substance classes discussed herein which have not previously been used as medicaments or diagnostics. In a further aspect, the invention relates to the use of an agent having the properties described herein for the preparation of a pharmaceutical composition for the treatment or prevention of tension-type headache.
In one aspect of the present invention the treatment or prevention of tension-type headache according to the invention is not accompanied by a substantial reduction of muscle tension.
In an important aspect the present invention relates to a method for treating tension-type headache in a person which comprises administering an agent in an amount effective to alleviate said headache, said agent being an agent capable of altering the relationship of pain intensity to pressure intensity when the trapezoid muscle is palpated at different pressure intensities in said person. The relationship is typically substantially linear in the untreated persons, and substantially non-linear in the treated persons. Furthermore, the relationship will typically be positively accelerating in the treated person. In one embodiment of the present invention the rate of acceleration of pain intensity with pressure intensity is substantially constant. In one important embodiment of the present invention the relationship in the treated persons is substantially the same as in control persons who did not have tension-type headache and who were treated with a placebo.
The agent interacting with neuronal transmission to substantially normalize an otherwise qualitatively altered stimulus/response function in connection with nociception is preferably one which directly quantitatively lowers pain perception, in that, in a panel of test persons suffering from increased myofascial tenderness with disorder of pericranial muscle in connection with tension-type headache, the administration of the agent will result in transformation of a substantially linear pain intensity perception in response to pressure intensity in trapezius as well as other relevant pericranial muscles into a curve (C) of which the values of pain intensity are lower than the linear pain intensity perception.
The curve (C) is preferably a curve which can be described substantially as a power function and is a curve which is substantially linear in a double logarithmic plot.
It is preferred that substantially each of the values of curve (C) is at the most 20% higher, preferably at the most 10% higher, than the value of the corresponding curve produced for a test panel of healthy controls.
In connection with any of the patient panel tests discussed above it is noted that the treatment with the agent in question should be performed by administration at least once daily to maintain a therapeutic plasma level in the patients and should be continued for a sufficient time to allow the agent to exert its therapeutic effect, but that an agent is considered not to perform according to the particular test if the effect is not obtained within a treatment time of three months. This does not mean that it will necessarily take three months for an agent to exert its therapeutic effect; some compounds will show their therapeutic effect after much shorter treatment periods, down to days or even hours. In connection with testing of a new candidate agent, the dosage of the agent will normally be kept as high as permitted by the toxicity of the compound during initial tests and will then be reduced to a lower level which is still maximally effective during the test proper.
Evaluation of the ability of an agent to provide an effective treatment for tension-type headache, by interacting with neuronal transmission according to the present invention, may also be performed as an acute test, in which the agent is administered, typically as a bolus or an infusion, to a group of patients suffering from chronic tension-type headache. In such a test, the pain connected to tension-type headache in these patients will typically be scored by the patients, as described in example 4, at various time points after administration of the agent, typically at least every 15 min and subsequently monitored over a period of at least 30 min, typically at least 60 min. preferably at least 90, more preferably at least 120 min. For the evaluation of a candidate agent, an additional group of patients acutely suffering from tension-type headache will receive placebo and serve as a control group. The curves based on the pain scores of patients in both groups will typically be compared, as shown in FIG. 14, and an agent will be considered effective in treatment of tension-type headache according to the present invention, if it is capable of preventing or substantially preventing pain in connection with tension-type headache when pain scores after administration of the agent, when differing most from the corresponding score after administration of placebo, are at least 10% lower than scores for placebo, typically at least 20% lower, preferably at least 30% lower, more preferably at least 40% lower. For an evaluation as described here, the size of the participating groups of patients will be at least 5 patients in each group, typically at least 7 patients in each group, preferably at least 10 patients in each group, more preferably at least 12 patients in each group, even more preferably at least 15 patients in each group.
Evaluation of the ability of an agent to provide an effective prevention of tension-type headache by interacting with neuronal transmission according to the present invention can be performed as described above except that the parameter measured and scored by headache patients will typically be duration of pain or frequency of pain in connection with tension-type headache in sufferers with an episodic form of the disease.
In the practical treatment of a patient, the administration of an agent will normally be continued for at least one month, preferably at least two months and more preferably at least three months and in many cases indefinitely in order to establish and maintain the normalization which is aimed at. If the desired normalization occurs before one month of treatment, it is certainly possible according to the invention to discontinue the treatment, but this will increase risk of relapse and is normally not preferred. The administration is performed using at least one dose daily or at any rate substantially at least one dose daily (which means that the treatment is not outside the scope of the invention if it is just interrupted one or perhaps even (but not preferred) a few days), and the dose of the particular agent is preferably adapted so that it will maintain a therapeutic plasma level substantially at any time. Notwithstanding the above statement to the effect that the administration may in many cases be performed indefinitely, it is contemplated that there will be cases where the treatment period will be less than 10 years, such as less than 5 years or less than 2 years or even less than 1 year.
The interaction with neuronal transmission connected with pain perception will normally be such an interaction with neuronal transmission connected with second order nociceptive neurons which involves substantially reducing excitation mediated through the interaction between transmitter substances and their receptors on second order nociceptive neurons.
The above-mentioned interaction will normally involve a reduction of C-fiber, A-d-fiber and A-b-fiber input to the nociceptive second order neurons, through a substantial reduction of excitatory activity in synapses of C-fibers, A-d-fibers and A-b-fibers on second order neurons, said activity mediated through the interaction between the involved transmitter substances and their receptors on second order nociceptive neurons.
The reduction of excitatory activity in synapses of C-fibers, A-d-fibers and A-b-fibers on second order neurons mediated through the interaction between the involved excitatory transmitter substances and their receptors on second order nociceptive neurons swill preferably be performed by administration of an effective amount of at least one agent which a) substantially inhibits the production of said excitatory transmitter substance, b) substantially inhibits the release of said excitatory transmitter substance, c) substantially counteracts the action of said excitatory transmitter substance, and/or d) substantially inhibits the binding of said excitatory transmitter substance to its relevant receptors.
Important examples of such excitatory transmitter substances are selected from the group consisting of glutamate, nitric oxide, neurokinins (substance P, neurokinin A, neurokinin B and bradykinin), CGRP, adenosine working through A2 receptors, 5-HT when working through 5-HT2,3 receptors and pituitary adenylate cyclase activating polypeptide (PACAP).
Agents which can interact with neuronal transmission mediated by glutamate will typically comprise competitive or non-competitive antagonists of ionotropic glutamate receptors, including NMDA, AMPA and kainate receptors. Interaction with glutamate neurotransmission can also be performed with antagonists at the glycine site of the NMDA receptors or with antagonists or inverse agonists at modulatory sites such as polyamine sites. Interaction with metabotropic glutamate receptors can be performed with agonists or antagonists depending on whether they are receptors located pre or postsynaptically and whether they belong to the excitatory type I receptors (mGluR1,5) or the inhibitory type II and type III receptors (mGluR2,3 and mGluR4,6-8, respectively).
While sensitization of second order neurons is believed, as explained above, to be an important cause of pain in connection with tension type headache, it is clear that other elements of neuronal transmission may also play a significant role and in some cases even a predominant role as explained in the model described in connection with FIG. 1. Based on this recognition, another, more general, aspect of the present invention introduces, for the first time, the use of a number of classes of substances for treatment of tension type headache. This aspect relates to a method for treatment or prevention of tension-type headache in a person in need of such treatment, comprising administering an amount of an agent which, in the peripheral and/or central nervous system, is effective to specifically interact with neuronal transmission connected with pain perception by
a) substantially antagonizing the action of glutamate, 5-HT, GABA, nitric oxide, nitric oxide synthase, guanylate cyclase, cyclic guanylate monophosphate (cGMP), CGRP, substance P, neurokinin A, neurokinin B, bradykinin, PACAB, adenosine, glycine, histamine, neurotrophins, Na+ ions or Ca2+ ion channels,
or by
b) substantially potentiating the action of adenosine, galanine or norepinephrine,
with the proviso that said agent is not ethyl 2-amino-6-(4-fluorobenzylamino)-3-pyridylcarbamate or an arylglycineamide derivative as described herein.
An additional aspect of the present invention relates to a method of treatment of tension-type headache comprising administering to a person in need of such treatment an effective amount of an agent which substantially inhibits the action of the enzyme nitric oxide synthase (NOS) and thereby reduces chronic pain in connection with tension-type headache. In many cases the effect of treatment of tension-type headache with a NOS inhibitor will be exerted through a decrease in existing central sensitization, but also within the scope of the invention is treatment of tension-type headache with NOS inhibitors whose effect on the reduction of pain in connection with tension-type headache is mediated through a mechanism not directly involving inhibition of central sensitization. Such an alternative mechanism might possibly comprise an alteration of pain modulation involving nitric oxide.
A very important aspect of the present invention is a method of screening a drug for the ability to alleviate a tension-type headache which comprises comparing the relationship of pain intensity to pressure intensity when the trapezoid muscle is palpated at different pressure intensities for (a) persons having tension-type headaches after treatment with the drug, and (b) persons having tension-type headaches, treated with a placebo, and determining if the relationship is altered. Also within the scope of the present invention is a method of screening a drug for the ability to alleviate tension-type headache comprising testing said drug in one or more of the assays 1-13 described above and determining effect in the test organism according to each assay. The test organisms will typically be human patients and human controls or relevant experimental animals, depending on the given assay.
In the following discussion of substances or groups of substances, numbers in parenthesis refer to the correspondingly numbered structural formulas in the formula sheets below. 
Agents which inhibit neuronal transmission mediated by glutamate, in the central and/or peripheral nervous system, are capable of a) substantially inhibiting the production of glutamate, b) substantially inhibiting the release of glutamate, c) substantially counteracting the action of glutamate and/or d) substantially inhibiting the binding of glutamate to receptors for glutamate.
Examples of competitive NMDA receptor antagonists are nitrogen-containing heterocyclic compounds selected from diacidic piperidines, such as CGS 19755 (1), diacidic piperazines, such as (R)-CPP (2) and (R)-CPPene (3), phosphono amino acids such as LY 235959 (4) and derivatives of any of the above which are competitive NMA antagonists or prodrugs thereof.
Examples of non-competitive NMDA receptor antagonists arc polycyclic amines, such as MK-801 (5); tricyclic antidepressants, such as Metapramine (6), Amitriptyline (7), Imipramine (8), Desipramine (9), Mirtazapine (10) or Venlafaxine (11); adamantanamines, such as Memantine (12); arylcyclohexylamines, such as Ketamine (13); arylcyclohexylamines, such as Norketamine (14), opioid derivatives, such Dextromethorphan (15); glycylamides, such as Remacemide (16); piperidinylethanols, such as Ifenprodil (17); piperidinylethanols, such as Eliprodil (18): diguanidines, such as Synthalin (19); xcex3-aminobutyric acid derivatives, such as Gabapentin (64), polycyclic amines, such as Pizotyline (83) or derivatives of any of the above which are non-competitive NMDA antagonists or prodrugs thereof.
Mirtazapine (10) and Venlafaxine (11) are conventionally known to have xcex1-2 receptor antagonist effects, and their efficacy as antidepressants are thought to be exerted through a decrease in noradrenergic neurotransmission. However, it is presently believed that Mirtazapine and Venlafaxine may also have an effect on glutamate neurotransmission, potentially as non-competitive NMDA receptor antagonists. It is through this mechanism that the two substances are presumed to provide a method of treatment of tension-type headache according to the present invention.
Examples of Glycine antagonists are aminopyrrolidinones, such as (R)-HA-966 (20); kynurenic acid derivatives, such as 7-Cl-Kynurenic acid (21); tetrahydroquinolines, such as L-689,560 (22); kynurenic acid derivatives, such as L-701,252 (23), L-701,273 (24), L-701,324 (25); indoles such as GV150526A (26); glycine derivatives, such as ACPC (27); quinoxalinediones, such as MNQX (28), ACEA 1021 (29) and DCQX (30); dicarbamates, such as Felbamate (31) and derivatives of any of the above which are glycine antagonists or prodrugs thereof.
Examples of competitive AMPA receptor antagonists are quinoxalinediones, such as CNQX (32), NBQX (33), PNQX (34) and YM90K (35); dihydroquinolones, such as L-698,544 (36); diacidic decahydroisoquinolines, such as LY 215490 (37); amino acid isoxazoles, such as AMOA (38); indoleoximes, such as NS-257 (39) and derivatives of any of the above which are competitive AMPA receptor antagonists or prodrugs thereof.
Examples of non-competitive AMPA receptor antagonists are 2,3-benzodiazepines, such as GYKI 52466 (40); phthalazines, such as SYM 2206 (41) and derivatives of any of the above which are non-competitive AMPA receptor antagonists or prodrugs there of.
Examples of competitive kainate receptor antagonists are indoleoximes, such as NS-102 (42) and derivatives thereof which are competitive kainic acid receptor antagonists or prodrugs thereof.
Examples of metabotropic receptor agonists are phenylglycines, such as 4CPG (43); amino acid indanes, such as UPF523 (44); phosphono amino acids, such as L-AP4 (45) and derivatives of any of the above which are metabotropic glutamate receptor agonists or prodrugs thereof.
Agents which inhibit neuronal transmission mediated by 5-HT, in the central and/or peripheral nervous system, are capable of a) substantially inhibiting the synthesis of 5-HT, b) substantially inhibiting the release of 5-HT, c) substantially counteracting the action of 5-HT and/or d) substantially inhibiting the binding of 5-HT to excitatory 5-HT, 5-HT2,3 receptors.
Examples of 5-HT2,3 receptor antagonists are tropan derivatives such as Tropanserin (82); polycyclic amines, such as Pizotyline (83) and derivatives of any of the above which are 5-HT2,3 receptor antagonists or prodrugs thereof.
It is presently believed that Pizotyline (83) may also have effect on glutamate neurotransmission, potentially as a non-competitive NMDA receptor antagonist, as mentioned above. This mechanism is presumed, in addition to the 5-HT receptor antagonism, to provide a method of treatment of tension-type headache according to the present invention.
Agents which can inhibit neuronal transmission mediated by adenosine, in the central and/or peripheral nervous system, are capable of a) substantially inhibiting the synthesis of adenosine, b) substantially inhibiting the release of adenosine, c) substantially counteracting the action of adenosine, and/or d) substantially functioning as antagonists at adenosine A2 receptors.
Examples of adenosine A2 receptor antagonists are xanthine derivatives, such as DMPX (80) and derivatives thereof which are A2 receptor antagonists or prodrugs thereof.
Examples of adenosine uptake inhibitors are homopiperazine derivatives, such as Dilazep (81) and derivatives thereof which are adenosine uptake inhibitors or prodrugs thereof.
Agents which can inhibit neuronal transmission mediated by substance P, in the central and/or peripheral nervous system are capable of a) substantially inhibiting the synthesis of substance P, b) substantially inhibiting the release of substance P, c) substantially counteracting the action of substance P, and/or d) substantially inhibiting binding of substance P to receptors for substance P.
Agents which can inhibit neuronal transmission mediated by neurokinin A, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the synthesis of neurokinin A, b) substantially inhibiting the release of neurokinin A, c) substantially counteracting the action of neurokinin A, and/or d) substantially inhibiting binding of neurokinin A to receptors for neurokinin A (NK2 receptors).
Examples of neurokinin A (NK2) receptor antagonists are peptidomimetics, such as SR-48968 (37); peptidomimetics, such as GR 159897 (38) and derivatives thereof which are NK2 receptor antagonists or prodrugs thereof.
Agents which can inhibit neuronal transmission mediated by bradykinin, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the production of bradykinin, b) substantially inhibiting the release of bradykinin, c) substantially counteracting the action of bradykinin and/or d) substantially inhibiting binding of bradykinin to receptors for bradykinin.
Examples of bradykinin receptor antagonists are peptidomimetics, such as Icatibant (48) and WIN 64338 (49) and derivatives of any of the above which are bradykinin receptor antagonists or prodrugs thereof.
Agents which can inhibit neuronal transmission mediated by CGRP, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the production of CGRP, b) substantially inhibiting the release of CGRP, c) substantially counteracting the action of CGRP and/or d) substantially inhibiting the binding of CGRP to receptors for CGRP.
Examples of CGRP receptor antagonists are CGRP 8-37.
Agents which can inhibit neuronal transmission mediated by PACAP, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the synthesis of PACAP, b) substantially inhibiting the release of PACAP, c) substantially counteracting the action of PACAP and/or d) substantially inhibiting binding of PACAP to receptors for PACAP.
Agents which can inhibit neuronal transmission mediated by nitric oxide, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the production of nitric oxide b) substantially counteracting the action of nitric oxide, c) substantially inhibiting the production of nitric oxide synthase (NOS) and/or d) substantially counteracting the action of nitric oxide synthase (NOS).
The interaction with neuronal transmission connected with pain perception connected with second order nociceptive neurons can comprise interaction with intracellular substances involved in this neuronal transmission, said interaction involving excitation mediated through the interaction with enzymes and second messengers in second order nociceptive neurons.
Preferred examples of the above mentioned intracellular substances are NOS, guanylate cyclase, and cGMP.
The interaction with neuronal transmission connected with pain perception, comprising interaction with NOS will preferably be performed by the administration of an effective amount of at least one agent which can substantially inhibit the production of the NOS, and/or substantially counteract the action of NOS.
Examples of NOS inhibitors are arginine derivatives, such as L-NAME (50), L-NMMA (51), L-NIO (52), L-NNA (53) and Dimethyl-L-arginine (54); citrulline derivatives, such as Thiocitrulline (55) and (S)-Methylthiocitrulline (56); indazoles, such as 7-Nitroindazole (57); imidazolin-N-oxides, such as Potassium carboxy-PTIO (58); phenylimidazoles, such as TRIM (59); 21-aminosteroids, such as Tirilazad (60); biphenyls, such as Diphenyleneiodinium chloride (61); piperidine derivatives, such as Paroxetine (62) and derivatives of any of the above which are NOS inhibitors or prodrugs thereof.
The interaction with neuronal transmission connected with pain perception, comprising interaction with guanylate cyclase can be performed by the administration of an effective amount of at least one agent, which substantially inhibits the production of guanylate cyclase and/or substantially counteracts the action of guanylate cyclase.
Examples of guanylate cyclase inhibitors are quinoxalines, such as ODQ (63) and derivatives thereof which are guanylate cyclase inhibitors.
The interaction with neuronal transmission connected with pain perception comprising interaction with cGMP can be executed by the administration of an effective amount of at least one agent which, in the peripheral and/or central nervous system, is capable or a) substantially inhibiting the production of guanylate cyclase, b) substantially counteracting the action of guanylate cyclase, c) substantially inhibiting the production of cyclic guanylate monophosphate (cGMP), d) substantially counteracting the action of cyclic guanylate monophosphate (cGMP) and/or e) substantially inhibiting any further steps in the reaction induced by cyclic guanylate monophosphate (cGMP), such as protein kinase C.
The activity of C-fibers, A-d-fibers and A-b-fibers on second order nociceptive neurons involves inhibitory neurotransmitter substances. Reduction of activity of C-fibers on second order neurons will normally be performed by administration of an effective amounts of at least one agent which is capable of a) substantially inhibiting the enzymatic degradation of said inhibitory transmitter substance, b) substantially enhancing the release of said inhibitory transmitter substance, c) substantially enhancing the action of said inhibitory transmitter substance and/or substantially activating the relevant receptor for said inhibitory transmitter substance.
Preferred examples of such inhibitory transmitter substances are selected from the group consisting of GABA, galanine, adenosine working through A1 receptors, and norepinephrine.
Agents which can stimulate neuronal transmission mediated by GABA, in the peripheral and/or central nervous system, are capable of a) substantially enhancing the production of GABA, b) substantially inhibiting the enzymatic degradation of GABA, c) substantially enhancing the release of GABA, d) substantially enhancing the action of GABA and/or e) substantially activating receptors for GABA.
An example of a substance with GAB-enhancing activity is benzodiazepines, such as Midazolam (69) and derivatives thereof which are GABA activity enhancers or prodrugs thereof.
Examples of GABA-A receptor agonists are xcex3-aminobutyric acid derivatives, such as Gabapentin (64) and TACA (65); Isonipecotic acid (66) and Isoguvacine (67); 3-hydroxyisoxazoles, such as THIP (68) and derivatives of any of the above which are GABA-A agonists or prodrugs thereof.
Gabapentin is conventionally known to have GABA-A receptor agonist activity, though this mechanism has been questioned. However, it is presently believed that Gabapentin may also have antagonist effect on glutamate transmission, indirectly or directly, potentially as a non-competitive NMDA receptor antagonist, as mentioned above. It is through this mechanism, in addition to its gabaergic activity, that Gabapentin is presumed to provide a method of treatment of tension-type headache according to the present invention.
Examples of GABA uptake inhibitors are carboxypiperidine derivatives, such as (xc2x1)-cis-4-Hydroxynipecotic acid (70); carboxypyridine derivatives, such as Guvacine (71); 3-hydroxyisoxazoles, such as THPO (72); nipecotic acid derivatives, such as SKF 89976-A (73) and Tiagabine (74); guavacine derivatives, such as NO-711 (75) and derivatives of any if the above which are GABA uptake inhibitors or prodrugs thereof.
Examples of GABA transaminase inhibitors are xcex3-aminobutyric acid derivatives, such as Vigabatrin (76) and derivatives thereof which are GABA transaminase inhibitors or prodrugs thereof.
Agents which can stimulate neuronal transmission mediated by galanine, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the enzymatic degradation of galanine, b) substantially enhancing the release of galanine, c) substantially enhancing the action of galanine and/or d) substantially functioning as agonists at galanine receptors.
Agents which can stimulate neuronal transmission mediated by adenosine, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the enzymatic degradation of adenosine, b) substantially enhancing the release of adenosine, c) substantially enhancing the action of adenosine and/or d) substantially functioning as agonists at A1 receptors.
Examples adenosine A1 receptor agonists are adenosine derivatives, such as N6-Cyclopentyladenosine (77); adeninglucosides, such as Adenosine (78) and derivatives thereof which are A1 receptor agonists or prodrugs thereof.
An example of an enhancer of the action of adenosine is pyrimidine derivatives, such as Dipyridamole (79) and derivatives thereof which are adenosine uptake inhibitors or prodrugs thereof.
Agents which can stimulate neuronal transmission mediated by norepinephrine, in the peripheral and/or central nervous system, are capable of a) substantially inhibiting the enzymatic degradation of norepinephrine, b) substantially enhancing the release of norepinephrine, c) substantially enhancing the action of norepinephrine and/or substantially functioning as agonists at norepinephrine xcex1-2 receptors.
Examples of xcex1-2 receptor agonists are aminoimidazolines, such as Clonidine (84); aminoimidazolines, such as Apraclonidine (85); thiazinamines, such as Xylazine (86); imidazoles, such as Dexmedetomidine (87) and derivatives of any of the above which are xcex1-2 receptor agonists or prodrugs thereof.
Reduction of activity of C-fibers on second order nociceptive neurons can be performed by administration of an effective amount of at least one agent which substantially blocks ion channels for Na+ or Ca2+ ions.
Examples of Na+ channel blockers are triazines, such as Lamotrigine (88); diphenylmethylpiperazines, such as Lifarizine (89); hydantoins, such as Phenytoin (90); aminopiperidines, such as Lubelnzole (91); benzthiazoles, such as Riluzole (92); dibenzazepines, such as Carbamazepine (93); phenylamides, such as Lidocaine (94); phenylamides, such as Tocainide (95); aminoethylanisoles, such as Mexiletene (96) and derivatives of any of the above which are Na+ it channel blockers or prodrugs thereof.
Examples of Ca2xe2x88x92 channel blockers are diphenylmethylpiperazines, such as Flunarizine (97); arylphosphonic esters, such as Fostedil (98) and derivatives of any of the above which are Ca2+ channel blockers or prodrugs thereof.
In accordance with normal usage the tern xe2x80x9cagentxe2x80x9d, as used herein, is intended to designate an active substance per se, whether administered as such or in the form of a prodrug thereof, as well as a pharmaceutical composition comprising the substance or prodrug.
In addition to the specific substances mentioned above, derivatives thereof which show an activity of the same kind as the substance specifically mentioned are also useful for the purpose of the present invention. The kind of derivatives which come into consideration will, of course, depend on the specific character of the substance in question, but as general examples of derivatives which may be relevant for many of the substances may be mentioned introduction of or change of alkylsubstituents (typically with a chain length from one to five carbon atoms on aliphatic chains, cycloalkanes, aromatic and heterocyclic ring systems, introduction of or change of substituents such as halogens or nitro groups, change of ringsize for cycloalkanes, change of aromatic or heterocyclic ringsystems, change of alkylsubstituents on O-and N-atoms change of the alcohol part of ester groups, and bioisosteric replacement of functional groups, especially use of carboxylic acid bioisosteres such as phosphonic acids, phosphinic acids, tetrazoles, 3-hydroxyisoxazoles, sulphonamiders and hydroxyamic acids. Salts of acidic or basic compounds will be equally useful compared to the free acids or free bases. In case of racemic compounds, can racemates as well as pure enantiomeres and diastereoisomeres be used, and in the case of substances interacting with antagonist action be required. Of course, derivatives to be used should be derivatives which, in addition to their desired activity, shown an acceptably low toxicity, and, in general, the derivatives should, just as the substances themselves, be pharmaceutically acceptable.
The agent used according to the invention may be administered as such or in the form of a suitable prodrug thereof. The tern xe2x80x9cprodrugxe2x80x9d denotes a bioreversible derivative of the drug, the bioreversible derivative being therapeutically substantially inactive per se but being able to convert in the body to the active substance by an enzymatic or non-enzymatic process.
Thus examples of suitable prodrugs of the substances used according to the invention include compounds obtained by suitable bioreversible derivatization of one or more reactive or derivatizable groups of the parent substance to result in a bioreversible derivative. The derivatization may be performed to obtain a higher bioavailability of the active substance, to stabilize an otherwise unstable active substance, to increase the lipophilicity of the substance administered, etc.
Examples of types of substances which may advantageously be administered in the form of prodrugs are carboxylic acids, other acidic groups and amines which may be rendered more lipophilic by suitable bioreversible derivatization. As examples of suitable groups may be mentioned bioreversible esters or bioreversible amides. Amino acids arc typical examples of substances which, in their unmodified form, may have a low absorption upon administration. Suitable prodrug derivatives of amino acids will be one or both of the above-mentioned types of bioreversible derivatives.
For the administration to a patient, a substance having any of the activities as defined above or a prodrug thereof is preferably formulated in a pharmaceutical composition containing one or more substances having any of the activities as defined above or prodrugs thereof and one or more pharmaceutically acceptable excipients.
The substance or substances to be administered may be formulated in the compositions in pharmaceutically acceptable media, the character of which are adapted to the chemical character of the substance. The compositions may be adapted for administration by any suitable method, for example by oral, buccal, sublingual, nasal, rectal or transdermal administration. Substances which are suitable for oral administration may be formulated as liquids or solids such as syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid compositions will normally comprise a suspension or solution of the substance in a suitable liquid carrier or suitable liquid carriers, for example an aqueous solvent such as water, ethanol or glycerol, or a non-aqueous solvent, such as polyethylene glycol or an oil. The composition may also contain a suspending agent, preservative, flavouring or coloring agent. A composition in the form or a tablet can be made using any suitable pharmaceutical carrier or carriers used for preparing solid formulations, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable non-toxic composition may be formed by incorporating normally used excipients, such as those carriers previously listed, and generally 1-95% of active ingredient that is, a substance used according to the invention or a prodrug thereof, often preferably 25-75% of the substance of the prodrug. A composition in the form of a capsule can be prepared using conventional encapsulation procedures. Thus, e.g., pellets containing the substance or prodrug in question may be prepared using any suitable carriers and then filled into a hard gelatin capsule, or a dispersion or suspension can be prepared using any suitable pharmaceutical carrier or carriers, such as aqueous gums, celluloses, silicates or oils and the dispersion or suspension can be filled into a soft gelatin capsule.
Examples of parenteral compositions are solutions or suspensions of the substances or prodrugs in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinyl pyrrolidene, lecithin, arachis oil or sesame oil. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as buffering agents, wetting agents, detergents, and the like. Additives may also include additional active ingredients, e.g. bactericidal agents, or stabilizers. If desired, the solution or suspension can be lyophilized and reconstituted with a suitable carrier such as a sterile aqueous carrier prior to administration.
Compositions for nasal administration can be formulated, e.g., as aerosols, drops, gels and powders. For aerosol administration, the substance or prodrug is preferably supplied in finely divided form along, with a surfactant and propellant. Typical percentages of the substance or prodrug are 0.01-20% by weight, preferably 1-10%. The surfactant must, of course, be non-toxic, and preferably soluble in the propellant. Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linoleic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arbitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides may be employed. The surfactant may constitute 0.1-20% by weight of the composition preferably 0.25-5%. The balance of the composition is ordinarily propellant. Liquified propellants are typically gases at ambient conditions, and are condensed under pressure. Among suitable liquified propellants are the lower alkanes containing up to 5 carbons, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes. Mixtures of the above may also be employed. In producing the aerosol, a container equipped with a suitable valve is filled with the appropriate propellant, containing the substance according to the invention and surfactant. The ingredients arm thus maintained at an elevated pressure until released by action of the valve.
Compositions for buccal or sublingual administration are, for example, tablets, lozenges and pastilles, in which the substance or the prodrug is formulated with a carrier such as sugar and acacia, tragacanth; or gelatin and glycerol. Compositions for rectal administration are suitably in the form of suppositories containing a suppository base such as cocoa butter. Compositions for transdermal application are for example ointments, gels and transdermal patches.
The compositions are preferably in unit dosage form such as a tablet, capsule or ampoule. Each dosage unit for oral administration will normally contain from 1 to 500 mg (and for parenteral administration preferably from 0.1 to 25 mg) of a substance used according to the invention or a prodrug therefore calculated as the free active substance.
The physiologically acceptable substances or prodrugs are normally administered in a daily dosage of between 1 mg and 500 mg for a adult person, usually between 10 mg and 400 mg, such as between 10 mg and 250 mg orally, or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 and 50 mg, such as between 1 mg and 25 mg of the substance. The substance or prodrug is preferably administered 1 to 4 times daily. As mentioned above, the administration is normally aimed at maintaining a therapeutically effective serum concentration of the substance for at least one month, preferably at least two months or at least three months. Controlled release type compositions will often be suitable for maintaining an effective serum concentration with a small number of daily unit dosages.